Preparation of Tryptanthrin Derivates Bearing a Thiosemicarbazone Moiety to Inhibit SARS-CoV-2 Replication
Abstract
:1. Introduction
2. Materials and Methods
2.1. Synthesis
2.1.1. Synthesis of Tryptanthrin (T8H)
2.1.2. Synthesis of Phaitanthrin A (PAA)
2.1.3. Synthesis of T8H-TSC
2.1.4. Synthesis of PAA-TSC
2.2. Derivates of Tryptanthrin Derivates and Metal Guests
2.3. Spectroscopic Studies on the Interactions of Tryptanthrin Derivates with Metal Guests
2.4. Determining the Conditional Binding Constants and the Complex Stoichiometry of Tryptanthrin Derivates with Cu(II), Fe(II) and Fe(III) Ions
2.5. Studying PAA-TSC, T8H-TSC and Their Copper Complex through Raman and Infrared Spectroscopy
2.6. Study of the Interaction of PAA-TSC and T8H-TSC Receptors with Cu(II) Ions by NMR
2.7. In Silico Docking of Tryptanthrins to CoV-2 Proteases
2.8. Antiviral Effects of T8H-TSC and PAA-TSC
3. Results and Discussion
3.1. Synthesis
3.2. Spectroscopic Study
FTIR, FT Raman and NMR Analysis of Cu Complex
3.3. In Silico Docking of PLpro and Mpro with Tested Tryptanthrins
3.3.1. Molecular Docking of PLpro with PAA, Tryptanthrin (T8H) and Their Derivates (PAA-TSC and T8H-TSC)
3.3.2. Molecular Docking of Mpro with PAA, Tryptanthrin (T8H) and Their Derivates (PAA-TSC and T8H-TSC)
3.4. Inhibition of SARS-CoV-2 Replication in Vero Cells
3.5. Lipinski’s Rule Analysis, Drug-likeness and Drug Score Factor
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
- Flora, S.J.; Pachauri, V. Chelation in metal intoxication. Int. J. Environ. Res. Public Health 2010, 7, 2745–2788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lawson, M.K.; Valko, M.; Cronin, M.T.D.; Jomová, K. Chelators in Iron and Copper Toxicity. Curr. Pharmacol. Rep. 2016, 2, 271–280. [Google Scholar] [CrossRef] [Green Version]
- Prachayasittikul, V.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V. 8-Hydroxyquinolines: A review of their metal chelating properties and medicinal applications. Drug Des. Dev. Ther. 2013, 7, 1157–1178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bleackley, M.R.; Macgillivray, R.T. Transition metal homeostasis: From yeast to human disease. Biometals 2011, 24, 785–809. [Google Scholar] [CrossRef]
- Tisato, F.; Marzano, C.; Porchia, M.; Pellei, M.; Santini, C. Copper in diseases and treatments, and copper-based anticancer strategies. Med. Res. Rev. 2010, 30, 708–749. [Google Scholar] [CrossRef]
- Diaz-Ochoa, V.E.; Jellbauer, S.; Klaus, S.; Raffatellu, M. Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis. Front. Cell. Infect. Microbiol. 2014, 4, 2. [Google Scholar] [CrossRef] [Green Version]
- Chen, A.Y.; Adamek, R.N.; Dick, B.L.; Credille, C.V.; Morrison, C.N.; Cohen, S.M. Targeting Metalloenzymes for Therapeutic Intervention. Chem. Rev. 2019, 119, 1323–1455. [Google Scholar] [CrossRef]
- Charbonnier, M.; González-Espinoza, G.; Kehl-Fie, T.E.; Lalaouna, D. Battle for Metals: Regulatory RNAs at the Front Line. Front. Cell. Infect. Microbiol. 2022, 12, 952948. [Google Scholar] [CrossRef]
- Bozkurt, F.T.; Tercan, M.; Patmano, G.; Bingol Tanrıverdi, T.; Demir, H.A.; Yurekli, U.F. Can Ferritin Levels Predict the Severity of Illness in Patients with COVID-19? Cureus 2021, 13, e12832. [Google Scholar] [CrossRef]
- Tabassum, T.; Araf, Y.; Moin, A.T.; Rahaman, T.I.; Hosen, M.J. COVID-19-associated-mucormycosis: Possible role of free iron uptake and immunosuppression. Mol. Biol. Rep. 2021, 49, 747–754. [Google Scholar] [CrossRef]
- Fratta Pasini, A.M.; Stranieri, C.; Girelli, D.; Busti, F.; Cominacini, L. Is Ferroptosis a Key Component of the Process Leading to Multiorgan Damage in COVID-19? Antioxidants 2021, 10, 1677. [Google Scholar] [CrossRef] [PubMed]
- Engin, A.B.; Engin, E.D.; Engin, A. Can iron, zinc, copper and selenium status be a prognostic determinant in COVID-19 patients? Environ. Toxicol. Pharmacol. 2022, 95, 103937. [Google Scholar] [CrossRef] [PubMed]
- Kaur, R.; Manjal, S.K.; Rawal, R.K.; Kumar, K. Recent synthetic and medicinal perspectives of tryptanthrin. Bioorg. Med. Chem. 2017, 25, 4533–4552. [Google Scholar] [CrossRef] [PubMed]
- Liang, Y.; Wang, X.; Fang, H.; Han, N.; Wang, C.; Xiao, Z.; Zhu, A.; Liu, J. A Highly Selective and Sensitive Colorimetric Probe for Cu2+ Determination in Aqueous Media Based on Derivative of Tryptanthrin. Anal. Sci. 2018, 34, 1111–1115. [Google Scholar] [CrossRef] [Green Version]
- Kawakami, J.; Kinami, Y.; Takahashi, M.; Ito, S. 2-Hydroxytryptanthrin and 1-Formyl-2-hydroxytryptanthrin as Fluorescent Metal-ion Sensors and Near-infrared Fluorescent Labeling Reagents. Trans. Mater. Res. Soc. Jpn. 2018, 43, 109–112. [Google Scholar] [CrossRef] [Green Version]
- Wang, Y.; Ai, Y.; Zhang, Y.; Ren, Y.; Wang, J.; Yao, F.; Li, W.; Zhou, Y.; Sun, Y.; Liu, J.; et al. A new probe with high selectivity and sensitivity for detecting copper ions in traditional Chinese medicine and water sample. Inorg. Chem. Commun. 2021, 128, 108563. [Google Scholar] [CrossRef]
- Kirpotina, L.N.; Schepetkin, I.A.; Hammaker, D.; Kuhs, A.; Khlebnikov, A.I.; Quinn, M.T. Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis. Front. Pharmacol. 2020, 11, 1145. [Google Scholar] [CrossRef]
- Kawakami, J.; Takahashi, M.; Ito, S.; Kitahara, H. Photophysical Properties of the 2-Hydroxytryptanthrin and Its Sodium Salt as Near-infrared Dyes for Fluorescent Imaging. Anal. Sci. 2016, 32, 251–253. [Google Scholar] [CrossRef] [Green Version]
- Popov, A.; Klimovich, A.; Styshova, O.; Moskovkina, T.; Shchekotikhin, A.; Grammatikova, N.; Dezhenkova, L.; Kaluzhny, D.; Deriabin, P.; Gerasimenko, A.; et al. Design, synthesis and biomedical evaluation of mostotrin, a new water soluble tryptanthrin derivative. Int. J. Mol. Med. 2020, 46, 1335–1346. [Google Scholar] [CrossRef]
- Tsai, Y.C.; Lee, C.L.; Yen, H.R.; Chang, Y.S.; Lin, Y.P.; Huang, S.H.; Lin, C.W. Antiviral Action of Tryptanthrin Isolated from Strobilanthes cusia Leaf against Human Coronavirus NL63. Biomolecules 2020, 10, 366. [Google Scholar] [CrossRef]
- Narkhede, R.R.; Pise, A.V.; Cheke, R.S.; Shinde, S.D. Recognition of Natural Products as Potential Inhibitors of COVID-19 Main Protease (Mpro): In-Silico Evidences. Nat. Prod. Bioprospect. 2020, 10, 297–306. [Google Scholar] [CrossRef] [PubMed]
- Mani, J.S.; Johnson, J.B.; Steel, J.C.; Broszczak, D.A.; Neilsen, P.M.; Walsh, K.B.; Naiker, M. Natural product-derived phytochemicals as potential agents against coronaviruses: A review. Virus Res. 2020, 284, 197989. [Google Scholar] [CrossRef]
- de Siqueira, L.R.P.; de Moraes Gomes, P.A.T.; de Lima Ferreira, L.P.; de Melo Rêgo, M.J.B.; Leite, A.C.L. Multi-target compounds acting in cancer progression: Focus on thiosemicarbazone, thiazole and thiazolidinone analogues. Eur. J. Med. Chem. 2019, 170, 237–260. [Google Scholar] [CrossRef] [PubMed]
- Shakya, B.; Yadav, P.N. Thiosemicarbazones as Potent Anticancer Agents and their Modes of Action. Mini Rev. Med. Chem. 2020, 20, 638–661. [Google Scholar] [CrossRef]
- Moharana, A.K.; Dash, R.N.; Subudhi, B.B. Thiosemicarbazides: Updates on Antivirals Strategy. Mini Rev. Med. Chem. 2020, 20, 2135–2152. [Google Scholar] [CrossRef] [PubMed]
- Gupta, S.; Singh, N.; Khan, T.; Joshi, S. Thiosemicarbazone derivatives of transition metals as multi-target drugs: A review. Results Chem. 2022, 4, 100459. [Google Scholar] [CrossRef]
- Dilworth, J.R.; Hueting, R. Metal complexes of thiosemicarbazones for imaging and therapy. Inorg. Chim. Acta 2012, 389, 3–15. [Google Scholar] [CrossRef]
- Dyrssen, D.; Ingri, N.; Sillén, L. “Pit-mapping”—A General Approach for Computer Refining of Equilibrium Constants. Acta Chem. Scand. 1961, 15, 694–696. [Google Scholar] [CrossRef] [Green Version]
- Jakubek, M.; Kejík, Z.; Antonyová, V.; Kaplánek, R.; Sýkora, D.; Hromádka, R.; Vyhlídalová, K.; Martásek, P.; Král, V. Benzoisothiazole-1,1-dioxide-based synthetic receptor for zinc ion recognition in aqueous medium and its interaction with nucleic acids. Supramol. Chem. 2019, 31, 19–27. [Google Scholar] [CrossRef]
- Jakubek, M.; Kejík, Z.; Kaplánek, R.; Veselá, H.; Sýkora, D.; Martásek, P.; Král, V. Perimidine-based synthetic receptors for determination of copper(II) in water solution. Supramol. Chem. 2018, 30, 218–226. [Google Scholar] [CrossRef]
- Jakubek, M.; Kejík, Z.; Parchaňský, V.; Kaplánek, R.; Vasina, L.; Martásek, P.; Král, V. Water soluble chromone Schiff base derivatives as fluorescence receptor for aluminium(III). Supramol. Chem. 2017, 29, 1–7. [Google Scholar] [CrossRef]
- Abramenko, N.; Kejík, Z.; Kaplánek, R.; Tatar, A.; Brogyányi, T.; Pajková, M.; Sýkora, D.; Veselá, K.; Antonyová, V.; Dytrych, P.; et al. Spectroscopic study of in situ-formed metallocomplexes of proton pump inhibitors in water. Chem. Biol. Drug Des. 2021, 97, 305–314. [Google Scholar] [CrossRef] [PubMed]
- Jakubek, M.; Kejik, Z.; Kaplanek, R.; Antonyova, V.; Hromadka, R.; Sandrikova, V.; Sykora, D.; Martasek, P.; Kral, V. Hydrazones as novel epigenetic modulators: Correlation between TET 1 protein inhibition activity and their iron(II) binding ability. Bioorg. Chem. 2019, 88, 102809. [Google Scholar] [CrossRef] [PubMed]
- Antonyova, V.; Kejik, Z.; Brogyanyi, T.; Kaplanek, R.; Vesela, K.; Abramenko, N.; Ocelka, T.; Masarik, M.; Matkowski, A.; Gburek, J.; et al. Non-psychotropic cannabinoids as inhibitors of TET1 protein. Bioorg. Chem. 2022, 124, 105793. [Google Scholar] [CrossRef] [PubMed]
- Antonyova, V.; Tatar, A.; Brogyanyi, T.; Kejik, Z.; Kaplanek, R.; Vellieux, F.; Abramenko, N.; Sinica, A.; Hajduch, J.; Novotny, P.; et al. Targeting of the Mitochondrial TET1 Protein by Pyrrolo 3,2-b pyrrole Chelators. Int. J. Mol. Sci. 2022, 23, 25. [Google Scholar] [CrossRef]
- Brogyanyi, T.; Kaplanek, R.; Kejik, Z.; Hosnedlova, B.; Antonyova, V.; Abramenko, N.; Vesela, K.; Martasek, P.; Vokurka, M.; Richardson, D.; et al. Azulene hydrazide-hydrazones for selective targeting of pancreatic cancer cells. Biomed. Pharmacother. 2022, 155, 12. [Google Scholar] [CrossRef]
- Brandão, P.; Pineiro, M.; Burke, A. Tryptanthrin and Its Derivatives in Drug Discovery: Synthetic Insights. Synthesis 2022, 54, 4235–4245. [Google Scholar] [CrossRef]
- Jao, C.-W.; Lin, W.-C.; Wu, Y.-T.; Wu, P.-L. Isolation, Structure Elucidation, and Synthesis of Cytotoxic Tryptanthrin Analogues from Phaius mishmensis. J. Nat. Prod. 2008, 71, 1275–1279. [Google Scholar] [CrossRef]
- Russell, R.; Beard, J.L.; Cousins, R.J.; Dunn, J.T.; Ferland, G.; Hambidge, K.; Lynch, S.; Penland, J.G.; Ross, A.C.; Stoecker, B.J.; et al. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc; National Academies Press: Washington, DC, USA, 2001. [Google Scholar]
- Morelli, B.; Peluso, P. Spectral Investigation on Ruthenium(III)-allyl Thiourea System. Anal. Lett. 1986, 19, 503–528. [Google Scholar] [CrossRef]
- Gambino, D.; Kremer, E.; Baran, E. Infrared spectra of new Re(III) complexes with thiourea derivatives. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2003, 58, 3085–3092. [Google Scholar] [CrossRef]
- Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010, 31, 455–461. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- BIOVIA. BIOVIA Discovery Studio Modeling Environment; BIOVIA: San Diego, CA, USA, 2017. [Google Scholar]
- Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera—A visualization system for exploratory research and analysis. J. Comput. Chem. 2004, 25, 1605–1612. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25.1. Adv. Drug Deliv. Rev. 2001, 46, 3–26. [Google Scholar] [CrossRef] [PubMed]
- Sander, T. The OSIRIS Property Explorer; Idorsia Pharmaceuticals Ltd.: Allschwil, Switzerland, 2001. [Google Scholar]
Name | Sequence 5′-3′ | Concentration in Reaction |
---|---|---|
E_Sarbeco_F1 | ACAGGTACGTTAATAGTTAATAGCGT | 400 nM |
E_Sarbeco_R2 | ATATTGCAGCAGTACGCACACA | 400 nM |
E_Sarbeco_P1 | FAM-ACACTAGCCATCCTTACTGCGCTTCG-BHQ1 | 200 nM |
Receptor | Ion | Log (K1) | Log (K2) | Stoichiometry (Metal Ion:Receptor) |
---|---|---|---|---|
PAA-TSC | Cu(II) | 8.9 | 15.0 | 1:1 2:1 |
Fe(II) | 1.5 | 13.7 | 1:1 1:2 | |
Fe(III) | 6.0 | 10.2 | 1:1 1:2 | |
T8H-TSC | Cu(II) | 4.6 | 8.1 | 1:1 1:2 |
Fe(II) | 4.9 | 7.1 | 1:1 2:1 | |
Fe(III) | 12.2 | 17.4 | 1:1 2:1 |
PAA | PAA-TSC | T8H | T8H-TSC | |
---|---|---|---|---|
Binding energy (kcal/mol) | −5.32 | −5.34 | −5.71 | −6.57 |
Ka/M/1000 | 7.9 | 8.2 | 15.3 | 65.4 |
PAA | PAA-TSC | T8H | T8H-TSC | |
---|---|---|---|---|
Binding energy (kcal/mol) | −6.32 | −7.94 | −7.2 | −8.56 |
Ka/M/1000 | 42.9 | 66.1 | 189.5 | 1882.2 |
Trypan. | H-Bond Acceptors | H-Bond Donors | Mw [Da] | cLogP | Polar Surface Area [A2] | Drug-Likeness | Drug Score |
---|---|---|---|---|---|---|---|
T8H | 4 | 0 | 248.24 | 1.73 | 49.74 | 3.28 | 0.94 |
PAA | 5 | 1 | 306.32 | 1.81 | 69.97 | 2.20 | 0.53 |
T8H-TSC | 6 | 2 | 321.36 | 1.67 | 115.17 | 3.89 | 0.92 |
PAA-TSC | 7 | 3 | 379.44 | 1.75 | 135.40 | 4.87 | 0.71 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Veselá, K.; Mělková, Z.; Abramenko, N.; Kejík, Z.; Kaplánek, R.; Dytrych, P.; Sinica, A.; Vozniuk, O.; Martásek, P.; Jakubek, M. Preparation of Tryptanthrin Derivates Bearing a Thiosemicarbazone Moiety to Inhibit SARS-CoV-2 Replication. Separations 2023, 10, 73. https://doi.org/10.3390/separations10020073
Veselá K, Mělková Z, Abramenko N, Kejík Z, Kaplánek R, Dytrych P, Sinica A, Vozniuk O, Martásek P, Jakubek M. Preparation of Tryptanthrin Derivates Bearing a Thiosemicarbazone Moiety to Inhibit SARS-CoV-2 Replication. Separations. 2023; 10(2):73. https://doi.org/10.3390/separations10020073
Chicago/Turabian StyleVeselá, Kateřina, Zora Mělková, Nikita Abramenko, Zdeněk Kejík, Robert Kaplánek, Petr Dytrych, Alla Sinica, Oleksandra Vozniuk, Pavel Martásek, and Milan Jakubek. 2023. "Preparation of Tryptanthrin Derivates Bearing a Thiosemicarbazone Moiety to Inhibit SARS-CoV-2 Replication" Separations 10, no. 2: 73. https://doi.org/10.3390/separations10020073